[31600-89-9]  · C7H7LiO  · o-Lithioanisole  · (MW 114.08)

(strong base/strong nucleophile capable of both nucleophilic addition and nucleophilic substitution)

Physical Data: the pKa for the ortho hydrogens in anisole has been estimated to be 39.0.4

Preparative Methods: by metalation of anisole in anhydrous ether with 2 equiv of n-Butyllithium and 2 equiv of N,N,N,N-Tetramethylethylenediamine at 25 °C for 1-2 h.1a Under these conditions a >95% conversion is obtained. If no excess of BuLi or other impurities can be tolerated, then the reagent can be prepared by metal halogen exchange of o-bromoanisole and purified by crystallization.1b Isolated o-lithioanisole is a pyrophoric white powder.

Form Supplied in: the reagent is prepared in situ as needed.

Handling, Storage, and Precautions: must be prepared and handled in an inert atmosphere, as for other organolithium reagents.

o-Lithioanisole as a Reagent.

Several factors influence the site and extent of metalation of an aromatic system containing a substituent group (DMG) that directs metalation.2 The methoxy group of anisole was the earliest such group to be identified.3 The important factors affecting the intrinsic (structural) effectiveness of such groups are: (1) the coordinating ability of the heteroatom in the DMG, (2) the electron-withdrawing (o-hydrogen-acidity enhancing) ability of the DMG,4 and (3) the size of the ring structure resulting from the formation of the coordinated o-lithio intermediate.5 The methoxy group occupies an intermediate position in the ranking of DMGs to direct metalation.

Early investigations of this reaction reported conversions of only 50-65% to the o-lithio intermediate.6,7 Later work revealed that the reaction could be accelerated by sonication,9 and by addition of a stoichiometric amount of N,N,N,N-Tetramethylethylenediamine (TMEDA),8 with a yield of 73% of the o-trimethylsilyl derivative being reported. A better procedure, that affords 95% (GC yield) of the o-trimethylsilyl derivative,1 involves use of 2 equiv each of n-Butyllithium and TMEDA. Concentration also plays a role; solutions of anisole in the 1M range appear to be best. Significantly lower amounts of TMEDA are nearly as effective in promoting the metalation. For highest yields the reaction is run at 25 °C in ether solvent for about one hour.

o-Lithioanisole formally contains only a four-membered coordinated ring system, although more elaborated structures involving the organolithium oligomer allow a pseudo five-membered ring to be drawn.5 Crystal structures of isolated complexes of o-lithioanisole10,11 exhibit tetrameric unit cells supporting the idea of a pseudo five-membered coordinated ring structure.12 For metalation solutions containing TMEDA, indirect NMR evidence and MNDO calculations favor an n-BuLi dimer-TMEDA-anisole interaction.5b Other efforts to understand the mechanism of the o-lithiation of anisole have been published.13,14

Two separate thermochemical studies have determined that o-lithioanisole is more stable than p-lithioanisole by either 1515 or 35 kJ mol-1.16 That the stability of the coordinated intermediate is important, or that interference with the ability to form such an intermediate is important in the transition state, can be adduced from several studies involving steric effects.6,17-19 The ability to generate the o-lithio intermediate for PhOR, where R is Me, Et, i-Pr, and t-Bu, falls off through the series.6,17

As stated earlier, the methoxy group is intermediate in its directing ability. A study of a series of p-substituted anisoles established the order CONHR, SO2NHMe, SO2NMe2, CH2NMe2 > OMe > F, CF3, CH2CH2NMe2.20 Subsequent reports added CONEt221 and oxazoline22 to the stronger- and SMe23 to the weaker-than-methoxy directing categories. Some additional ordering within the categories has been established as well as certain other directing groups added to each of the categories.1,2

A number of other monosubstituted anisoles have been metalated. Varying yields of product derived from metalation ortho to the methoxy group have been obtained from p-F,24-27 p-Cl,24,28 p-Br,24 and p-I24 anisole. The best yields that can be obtained from these systems lie in the 50-60% range because of the opportunities for various side reactions involving the halogens. p-Methylanisole has been metalated in about 30% yield29 and 1,4-dimethoxybenzene in about 75% yield.8 The latter compound, by the addition of TMEDA to the metalation system, can be made to form a 2,5-dilithio intermediate.

Two interesting and potentially useful reversals of the site of metalation have been developed. For p-methoxydimethylbenzylamine the preferred site of metalation with n-BuLi is that ortho to the dimethylaminomethyl group. However, when TMEDA is added to the metalation system, the preferred site of metalation is ortho to the methoxy group.30 Both o-and p-fluoroanisole can be made to exhibit the same phenomenon. With n-BuLi, metalation occurs exclusively ortho to the methoxy group,26,27 while at -78 °C with n-BuLi/N,N,N,N,N-Pentamethyldiethylenetriamine, metalation takes place ortho to the fluoro substituent.26

Disubstituted benzenes exhibiting an ortho- or meta-orientation of directing substituents can be successfully metalated. 1,2-Dimethoxybenzene easily affords the 3-substituted product of metalation while 1,3-dimethoxybenzene undergoes metalation specifically at the 2-position.8 Similarly, 3-fluoroanisole, if metalated at -78 °C, provides derivatives at the 2-position.31 For the hydroxyanisoles, mixtures were obtained for the metalation of the 1,2- and 1,3-isomers, but fairly regiospecific metalation ortho to the methoxy group was obtained for the 1,4-isomer.32

1-Methoxynaphthalene upon treatment with n-BuLi/TMEDA affords 2-metalation; with t-Butyllithium/pentane, 8-metalation is achieved.33 2-Methoxynaphthalene undergoes metalation at the 3-position.34 Certain methoxy heterocycles have also undergone successful directed metalation, although the yields are usually modest. 2-Methoxypyridine has been derivatized in the 3-position using a novel metalating system: Methyllithium catalyzed by a small amount of Diisopropylamine. This mixture of a kinetic and thermodynamic base avoids the competition of addition of RLi to the pyridine system.35 3-Methoxythiophene has been metalated in the 2-position36 and 2,4-dimethoxypyrimidine in the 5-position using Lithium Diisopropylamide or Lithium 2,2,6,6-Tetramethylpiperidide.37 Methoxyferrocene is metalated with n-BuLi in the 2-position.38

A number of directing groups related to the methoxy group also provide good yields of the o-lithio intermediate. These include the methoxymethoxy group (OCH2OMe),39 the carbamate group (OC(O)NEt2)2,40 the methoxyethoxy group (OCH2CH2OMe),41,44 the 2-(trimethylsilyl)ethoxymethoxy system (OCH2OCH2CH2SiMe3),42 and the dimethylaminoethoxy group (OCH2CH2NMe2).43,44 Some of these derivatives can be transformed into the phenol upon hydrolysis or other suitable treatment. Lastly, phenol itself can undergo o-lithiation.45 For the first three of the above-named directors the yields of o-lithiation are good.

More complex examples of the o-lithiation of substituted anisoles illustrate the utility of the reaction for synthesis. In the preparation of a series of phenethylamines the key precursor, 5-methoxybenzonorbornadiene, was generated from m-fluoroanisole (eq 1).46 Using a one-pot lithiation/oxygenation procedure (s-Butyllithium, TMEDA; then Oxygen) a series of methoxyphenols was prepared by direct hydroxylation in modest yields (eq 2).47 Veratrole can be metalated and alkylated cleanly (eq 3).48 Double metalation of anisole has led to a trisubstituted aryloxazoline (eq 4).49 A centrally acting dopaminergic and serotoninergic agonist was synthesized by metalation/hydroxylation of a methoxytetralin (eq 5).50 A total synthesis of the naturally occurring sesquiterpene, aplysin, in its racemic modification was accomplished by a surprisingly regiospecific metalation of a bromoanisole (eq 6). 51 Cram and co-workers have utilized the o-lithiation of a dimethoxybiphenyl in the synthesis of cavitands and caviplexes (eq 7).52

Examples of the utility of directing groups related to the methoxy group can also be found in the literature. A bipyridine derivative has been used to synthesize orelline, a toadstool metabolite. A test reaction established a fairly efficient bis-metalation of the bipyridine (eq 8).53 In order to avoid lateral metalation of the methyl group, the methoxymethoxy group was utilized in the first step of a synthesis of anthramycin (eq 9).54

Regiospecific metalation of tamoxifen, an antiestrogenic agent currently employed in the treatment of breast cancer, has been utilized to synthesize an o-iodo derivative (derived from the o-Sn precursor); this technique has the potential of introducing a radioactive label (eq 10).55 Utility of the carbamate group has recently been reviewed.2b

Related Reagents.

Lithium 2-Lithiophenoxide; Phenyllithium.

1. (a) Slocum, D. W.; Moon, R.; Thompson, J.; Coffey, D. S.; Li, J. D.; Slocum, M. G.; Siegel, A.; Gayton-Garcia, R. TL 1994, 35, 385. (b) Glaze, W. H.; Ranade, A. C. JOC 1971, 36, 3331.
2. (a) Gschwend, H. W.; Rodriquez, H. R. OR 1979, 26, 1. (b) Snieckus, V. CRV 1990, 90, 879.
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4. A determination of the acidity of a number of o-H's in certain substituted benzenes has been published: (a) Fraser, R. R.; Bresse, M.; Mansour, T. S. CC 1983, 620. (b) Fraser, R. R.; Bresse, M.; Mansour, T. S. JACS 1983, 105, 7790.
5. The o-lithio intermediate formed from the metalation of anisole contains, formally, a four- or a pseudo five-membered ring. For an initial proposal of a pseudo five-membered ring intermediate, see: (a) Slocum, D. W.; Sugarman, D. I. In Polyamine-Chelated Alkali Metal Compounds; Langer, A. W., Ed.; American Chemical Society: Washington, 1974; p 232. For a more recent consideration of the question of ring size, see: (b) Bauer W.; Schleyer, P. v. R. JACS 1989, 111, 7191.
6. Finnegan, R. A.; Altschuld, J. W. JOM 1967, 9, 193.
7. Shirley, D. A.; Johnson, Jr. J. R.; Hendrix, J. P. JOM 1968, 11, 209
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9. Einhorn, J; Luche, J. L. JOC 1987, 52, 4124.
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26. Katsoulos, G.; Takagishi, S.; Schlosser, M. SL 1991, 731.
27. Slocum, D. W.; Coffey, D. S.; Siegel, A.; Grimes, P. TL 1994, 35, 389.
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29. Letsinger, R. L.; Schnizer, A. W. JOC 1951, 16, 869.
30. Slocum, D. W.; Book, G.; Jennings, C. A. TL 1970, 3443.
31. (a) Adejare, A.; Miller, D. D. TL 1984, 25, 5597. (b) For a theoretical discussion, see: Saa, J. M.; Deya, P. M.; Suner, G. A.; Frontera, A. JACS 1992, 114, 9093.
32. Morey, J.; Costa, A.; Deya, P. M.; Suner, G; Saa, J. M. JOC 1990, 55, 3902.
33. Shirley, D. A.; Cheng, C. F. JOM 1969, 20, 251.
34. Sunthankar, S. V.; Gilman, H. JOC 1951, 16, 8.
35. Trecourt, F.; Mallet, M.; Marsais, F.; Queguiner, G. JOC 1988, 53, 1367.
36. Jen, K.-Y.; Eckhardt, H.; Jow, T. R.; Shacklette, L. W.; Elsenbaumer, R. L. CC 1988, 215.
37. Wada, A.; Yamamoto, J.; Hamaoka, Y.; Ohki, K.; Nagai, S.; Kanatomo, S. JHC 1990, 27, 1831.
38. Slocum, D. W.; Koonsvitsky, B. P.; Ernst, C. R. JOM 1972, 38, 125.
39. (a) Ronald, R. C.; Winkle, M. R. T 1983, 39, 2031. (b) Furukawa, Y.; Yamagiwa, Y.; Kamikawa, T. CC 1986, 1234. (c) Townsend, C. A.; Bloom, L. M. TL 1981, 22, 3923. (d) Harvey, R. G.; Cortez, C.; Ananthanarayan, T. P.; Schmolka, S. JOC 1988, 53, 3936.
40. Sibi, M. P.; Snieckus, V. JOC 1983, 48, 1935.
41. Ellison, R. A.; Kotsonis, F. N. JOC 1973, 38, 4192.
42. Sengupta, S.; Snieckus, V. TL 1990, 31, 4267.
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48. Ng, G. P.; Dawson, C. R. JOC 1978, 43, 3205.
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Donald W. Slocum

Western Kentucky University, Bowling Green, KY, USA

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